1. Field of the Invention
The invention relates to therapeutic compositions for the treatment of cancer. More particularly, the invention relates to the therapeutic treatment of cancers which express the MUC-1 antigen.
2. Summary of the Related Art
The tumor-associated antigen MUC1 is a high-molecular weight glycoprotein that is expressed on many adenocarcinomas. Gendler, et al., J. Biol. Chem. 265:15286, 1990, Gendler, et al., P.N.A.S. U.S.A., 84:6060, 1987, Siddiqui, et al., P.N.A.S. U.S.A. 85:2320, 1988, and Ligtenberg, et al., J. Biol. Chem. 265:5573, 1990 teach that the extracellular domain of the integral membrane glycoprotein consists mainly of 30 to 90 tandem repeats of a 20 amino acid core sequence that is rich in serine, threonine and proline, GSTAPPAHGVTSAPDTRPAP (SEQ ID NO:1). Burchell, et al., Cancer Surv. 18:135, 1993, teaches that the number of repeats expressed by an individual is genetically determined, resulting in size polymorphism.
Price, et al. Breast 2:3, 1993, teaches that the minimum sequence recognition of most MUC1 reactive monoclonal antibodies all lie within APDTRPAP (SEQ ID NO:2), which is believed to be a type 1 xcex2-turn. Burchell, et al. Cancer Surv. 18:135, 1993, discloses that the sequence SAPDTRP (SEQ ID NO:3) in the MUC1 tandem repeat is an immunodominant B cell epitope and that a T cell epitope of the tandem repeat has been mapped to the pentamer, PDTRP (SEQ ID NO:4). Adjacent amino acids and sugar residues may play an important role in the binding in the native molecule. A large number of tandem repeats may be present in the MUC1 mucin, ranging between 30 and 90 per molecule.
Tumor MUC-1 are generally hypoglycosylated and the glycosylation sites often have aberrant sugar chain extensions. Magnani, et al., Cancer Res. 43:5489, 1983, teaches that this aberrant glycosylation results in the exposure of normally cryptic peptide epitopes and the creation of novel carbohydrate epitopes. Because of their high molecular weight (2xc3x97105-5xc3x97107 dalton) as well as extensive glycosylation, cell membrane mucins exist as flexible rods and protrude at a relatively great distance from the cell surface. Mucins thus form an important component of the glycocalyx and are probably the first point of cellular contact with antibodies and cells of the immune system.
Rittenhouse, et al., Lab. Med. 16:556, 1985; Price, et al., Breast 2:3, 1993; Metzgar, et al., P.N.A.S. U.S.A. 81:5242, 1984; Magnani, et al., Cancer Res. 43:5489, 1983; Burchell, et al., Int. J. Cancer 34:763, 1984; Linsley, et al., Cancer Res. 46:5444, 1986; and Neutra, et al., in Physiology of the Gastrointestinal Tract, Johnson, L. R. ed., 2 edition, Raven Press, New York, p 975-1009, 1987, teach that normal tissue mucins are usually only displayed and secreted on the apical surfaces of epithelial cells, specifically, the mucosal surfaces. Ho, et al., Cancer Res. 53:641, 1993, teaches that the MUC1 mucin is highly expressed on the apical membranes of bronchus, breast, salivary gland, pancreas, prostate, and uterus, and sparingly expressed on gastric surface cells, gall bladder, small intestine and colonic epithelium. Cell surface MUC-1 may serve important functions, including protection against proteolytic degradation and providing a barrier against microbial toxins. Jentoff, Trends Biol. Sci. 15:291,1990; Parry, et al., Exp. Cell Res. 188:302, 1990; Wong, et al., J. Immunol. 144:1455, 1990; Devine and Mackenzie, BioEssays 14:619, 1993 teach that they can also serve as lubrication for epithelial surfaces, presentation of carbohydrate receptors for micro-organisms to assist in their elimination, for selection of symbiotic strains in competition with pathogens, for transmembrane signal-transduction, cell-cell interactions, regulation of cell growth, as well as maintenance of polarity.
Tumor mucins are thought to serve a critical function for tumor survival in the body. They may protect tumor cells from the low pH caused by high metabolic activity within the tumor. MUC1 is thought to inhibit tumor cells from forming tight aggregates with the tumor tissue thereby increasing metastatic potential. Regimbald et al., Cancer Res. 56:4244, 1996, teaches that MUC1 is involved in the homing of circulating tumor cells to distant sites by its molecular interaction with ICAM1 present on normal cells.
Mucins may also protect tumor cells from recognition by the immune system. Devine and MacKenzie, BioEssays 14:619, 1993, teaches that when MUC-1 are shed into the circulation, they may play a role in the observed tumor-specific immune-suppression possibly by providing steric hindrance to cell surface antigens to cellular and humoral immune effectors. Codington, et al., in Biomembranes, Mansoe, L. A., ed., Plenum Pub. Corp, New York, pp 207-259, 1983; Miller, et al., J. Cell Biol. 72:511, 1977; Hull, et al., Cancer Commun. 1:261, 1989, teach that cell membrane MUC-1 can mask other cell-surface antigens and protect cancer cells from immune attack.
Rising concentrations of tumor-associated MUC-1 in the patient""s serum have also been correlated with increasing tumor burdens indicating progression of disease. Price et al., Breast 2:3, 1993 and Pihl et al., Pathol. 12:439, 1980, teach that high serum levels of MUC-1 are correlated with poor prognosis in cancer patients.
There is, therefore, a need for new therapeutic compositions which can selectively bind tumor-associated MUC-1 and reduce, reverse or prevent their effects in cancer. Kufe, U.S. Pat. No. 5,506,343, 1996, teaches that tumor-associated MUC-1 antibody specificity can only be achieved when fully unglycosylated peptide is recognized by the antibody. Unfortunately, however, this antibody has not been shown to be therapeutically effective against a tumor that expresses a tumor-associated MUC-1. While tumor-associated MUC-1 has reduced and altered glycosylation, they still retain carbohydrate structures specific for the cancer. There is, therefore, a particular need for a therapeutic composition that comprises a binding agent that can bind to an epitope of a MUC-1 that includes both peptide and tumor specific carbohydrate.
The invention provides therapeutic compositions comprising binding agents that specifically bind to tumor-associated MUC-1 and reduce, reverse or prevent their effects in cancer. More particularly, the invention provides therapeutic compositions that comprise a binding agent that can specifically bind to an epitope that comprises both peptide and carbohydrate on such tumor-associated MUC-1. The invention further provides methods for the use of such therapeutic compositions in the treatment of cancer. The present inventors have surprisingly discovered that the relative specificity for tumor associated MUC-1 is not necessarily sacrificed in the case of binding agents that recognize an epitope that includes carbohydrate. The compositions and methods according to the invention provide new promise for therapeutic treatment of tumors that produce tumor-associated MUC-1 antigens.
In a first aspect, the invention provides therapeutic compositions comprising binding agents that specifically bind to tumor-associated MUC-1 and that are effective in reducing tumor burden or prolonging survival in a mammal having a tumor that expresses a tumor-associated MUC-1. In certain preferred embodiments, the MUC-1 is human MUC-1. Preferred binding agents bind specifically to MUC-1 epitopes that include carbohydrate. Particularly preferred binding agents include peptides or peptidomimetics, including antibodies and antibody derivatives.
In a second aspect, the invention provides methods for therapeutically treating a mammal bearing a tumor that comprises tumor-associated MUC-1 antigen. The methods according to this aspect of the invention comprise administering to the mammal an effective amount of a binding agent according to the invention. Preferably, the binding agent is administered intravenously or subcutaneously at low dosages.